Acne vulgaris is a common disease which afflicts approximately 90% of all teenagers, and, not uncommonly, affects men and women in their twenties or thirties or may persist in adults for many years. Acne vulgaris most commonly occurs on oily areas of the skin with high sebaceous gland concentration. The areas of high sebaceous gland concentration are the face, ears, retroauricular areas (e.g. behind the ears), chest, back, and occasionally the neck and upper arms.
Acneiform eruptions can occur wherever there is a pilosebaceous unit or sebaceous follicle which does include the entire surface of the skin.
The basic lesion in acne is the comedo commonly known as the blackhead. The comedo is created by retention of layers of dead skin known as keratin in the lining of the follicles. In addition to hyperkeratosis (which is thickening or retentative layering of keratin), there is an accumulation of sebum which is the lipid-laden product of the sebaceous gland. The cells of the sebaceous glands in which sebum originates are the sebocytes. The combination of the keratin and the sebum produces a plugging of the mouth or opening of the follicular canal, and papules are formed by inflammation around the comedones (plural of comedo). Depending upon the degree of inflammation, pustules, cysts, nodules, granulomatous reactions, scars, and keloids may develop.
Most typical forms of mild acne vulgaris demonstrate the predominance of comedones with the occasional pustules. Pustules and papules predominate in more severe cases. These can heal with scar formation; that is, fibrosis of the lesions which are deep and penetrating. In moderately active cases, larger cystic lesions can develop.
Acne vulgaris can appear in many clinical varieties. The mildest case manifests comedones on oily skin and is called acne comedo.
Papular acne is another variety of acne which has many inflammatory papules. This form of acne is common in adolescent skin, but it can be seen in all ages. The papular inflammatory form of acne can progress to an indurated, deeper, and destructive form known as acne indurata. These lesions can produce severe scarring and can be quite deep seated and destructive.
Steroid acne vulgaris can occur when oral corticosteroids or topical steroids are used and occurs as inflammatory follicular papules. When oral corticosteroids are ingested, the inflammatory papules are usually sudden in appearance and can cover the chest, back, arm, and face. When topical corticosteroids are used for more than two weeks, a localized inflammatory papular response can develop which can proceed to a granulomatous chronic reaction known as steroid acne rosacea.
Premenstrual acne can occur in a large number of menstruating women as a papular and pustular acne vulgaris, approximately one week prior to menstruation. There is a body of evidence that implicates a surge in progesterone as the mediator of premenstrual acne.
Preadolescent acne is divided into neonatal, infantile, and childhood forms of acne. The neonatal form is limited to the first few weeks of life. It usually develops a couple of days after birth. It more commonly afflicts males and reveals transient facial papules and pustules which can clear spontaneously in a few days or weeks. The stimulation of neonatal sebaceous glands by circulating maternal progesterone appears to be the cause.
If the acne persists beyond the first month of life, the acne is called infantile acne and can extend into childhood, adolescence, and adult life. The childhood acne can result from a persistent infantile acne or can develop de novo after age two. This form of acne is uncommon, but it has more of a male predeliction. It is characterized by comedones commonly in groups, papules, pustules, and, rarely, cysts. This condition can extend from a few weeks to several years and can develop into pubertal acne.
Acne venenata is by definition a comedonal or papular acne which occurs after exposure to chlorinated hydrocarbons (chloracne), cutting oils, petroleum oil, coal tar, and pitches.
Acne cosmetica is a persistent low grade comedonal and/or papular and pustular acne that occurs usually on the chin and cheeks of adult women due to oil-based cosmetics, i.e. foundations, facial creams, and sunscreens.
Pomade acne is a type of acne cosmetica which appears to occur almost exclusively in black persons who apply grease and oil to scalp hair and the face as a grooming aid. The lesions are predominately comedonal acne and can develop into inflammatory acne papules, depending upon the chronicity of the pomade use.
Acne detergicans occurs as a type of comedonal acne in patients who use oil-based cleansing soaps. Acne excoriee, also known as pickers acne, starts out as a mild form of papular or comedonal acne which is manipulated or picked and causes further inflammation, more papules, and sometimes scars, pitting, and atrophy of the skin.
Gram negative acne, sometimes called gram negative folliculitis when it extends to the neck, arms, legs, and trunk, is a form of an inflammatory papular, follicular, and pustular response to gram negative organisms including Enterobacter, Klebsiella, Escherichia, Proteus, Serratia, and Pseudomonas. The most characteristic lesion on the face are superficial pustules, or papulo-pustules (which is a combination of a papule and pustule). The face can show diffuse erythema and inflammation surrounding these pustules and juicy papules or papulo-pustules.
The gram negative acne is usually highly resistant and usually occurs in patients who have bad inflammatory papular acne for long periods or who have been treated with long term oral administration of antibiotics such as tetracycline, erythromycin, or minocycline or topical antibiotics such as topical clindamycin or topical erythromycin. Subsequent to the oral administration of tetracycline or erythromycin, oral administration of amoxicillin, ampicillin, and trimethoprim-sulfomethoxazole has been shown to be effective in treating this disease. (Poli, F., Prost, C., Revuz, J., Gram-negative Folliculitis, Ann. Dermatol. Venereol., 115:797-800, 1988).
In another reference, Marks, R. and Ellis, J., "Comparative effectiveness of tetracycline and ampicillin in rosacea", Lancet, 1971, vol. 2, pages 1049-1052, there is a disclosure that ampicillin has been used orally for treatment of rosacea. More specifically, orally administered ampicillin was compared with orally administered tetracycline in the treatment of rosacea.
Furthermore, in the personal experience of one of the inventors, in his capacity as a practicing dermatologist, in treating well over 200 patients, oral ampicillin taken in the form of an oral capsule between 500 mg and 1 gm each day for one month greatly improves this condition. Before treatment with ampicillin orally, the patients appear to have inflammatory papules and pustules present, and treatment of this clinical subset of acne vulgaris appears to have good success with the oral ampicillin.
However, unwanted side effects often occur with the oral administration of ampicillin (and amoxicillin). For example, unwanted side effects from oral administration often include diarrhea, cramping, and nausea. It would be desirable, therefore, to provide a treatment with ampicillin (and amoxicillin) which does not result in the unwanted side effects stated above.
Acne rosacea is an inflammatory eruption that is chronic and occurs on the face, especially on the nose as well as the scalp and neck, in some instances. It is manifested by erythema, pustules, papules, telangiectasia (which is dilation of superficial capillaries), and hypertrophy of sebaceous glands. The middle portions of the face are most frequently involved. The eyes and eyelids are not uncommonly involved and can produce inflammation and infection of the conjunctiva, eyelids, and hypertrophy of the meibomian glands. Acne rosacea is often called simply rosacea and is most common in middle aged women and men. Rosacea can go on to form a granulamatous rosacea which is characterized by resistant inflammatory papules which when biopsied reveal noncaseating epithelial cell granulomas.
Pseudofolliculitis barbae is a predominantly male affliction which is characterized by inflammatory papules and pustules on the bearded area of the face most commonly in black persons, but all racial groups can be affected. The mechanism is thought to be an inflammatory response to the end of hair (usually curly beard facial hair) into the skin causing a foreign body inflammatory response.
Folliculitis is an inflammatory reaction around the hair follicule which can be bacterial or nonbacterial in nature. Predominately, folliculitis is caused by gram positive organisms such as Staphylococcus and Streptococcus, and less frequently by gram negative bacteria discussed hereinabove with respect to gram negative folliculitis.
Perioral dermatitis is a common papular inflammatory eruption which is confined around the mouth. It most commonly afflicts women in their early twenties to middle thirties, but it can be seen in adolescents and more mature adults.
Hiddradenitis suppurativa is a suppurative (chronic) and cystic disease of apocrine gland regions of the skin, including the axillae, perineum and groin.
There is a genetic tendency to acne, in particular acne congoblata which is a deep cystic and sinus forming type of acne. This condition is essentially a deep, aggressive form of cystic acne occurring in the apocrine gland regions. Topical administration of clindamycin has been used to treat this form of cystic acne.
The etiology of acne vulgaris and related disorders as discussed above is not completely known in every detail. However, what is known is that acne, in general, is caused by a plurality of factors. In general, there are four main factors that cause acne: genetics; hormonal activity; bacteria; and the inflammatory response.
Genetics is a prominent component as it is well known that several members of the same family can be affected with moderate to severe scarring acne. The inheritance by some is thought to be autosomal dominant, but this has not been definitively proven. Furthermore, on the molecular level, there has not yet been discovered a gene or group of genes that are responsible for the various forms of acne vulgaris.
Another key factor in the development of acne is hormonal. In adolescence, for example, it is thought that androgens can interact with receptors on the sebaceous glands and cause stimulation of the sebaceous gland, to hypertrophy and hence form more sebaceous production of lipids and free fatty acids which distend the follicular canal. More specifically, there is evidence for increased peripheral metabolic conversion of the androgen testosterone to dihydrotestosterone at the level of the skin in acne patients. It is further hypothesized that receptors on the sebaceous gland for the active androgen dihydrotestosterone can exhibit various degrees of sensitivity, and that a heightened sensitivity response may be partially or entirely genetically predetermined.
Another causative factor in acne is the presence of bacteria in the follicular canal. Within the follicular canal are bacteria which are indigenous to the follicular lining. Among the bacteria flora present are anaerobic, gram positive organisms called Proprionibacterium acnes. It is interesting to note that they are present in abundance in pathologically affected sites. They are reduced during oral antimicrobial treatment, and their absence from nonhuman animal skin is striking especially since animals do not exhibit acne vulgaris.
Yet another causative factor in acne is the inflammatory response manifested in the skin. More specifically, it is thought that Proprionibacterium acnes lives in symbiosis on the keratin lined follicular canal. Proprionibacterium acnes ingests the sebum produced from the sebocytes of the sebaceous glands. This nascent sebum is largely lipid in composition and also contains DNA, RNA, proteins, and other cellular components that result from the breakdown of sebocytes themselves. The Proprionibacterium acnes which are highly lipophilic, feed on the nascent sebum. It has been shown that Proprionibacterium acnes are found only in sebaceous rich areas. If the nutrients increase due to an active and large sebaceous system, then colonization and high growth rates of Proprionibacterium acnes will form. It has been shown that the resident bacterial flora will produce biologically active molecules such as histamine, extracellular enzymes, and peptides which may be responsible for the chemotaxis of the inflammatory infiltrate in acne vulgaris. Since the follicular lining in the pilosebaceous unit is intact, it has been theorized that if colonization of Proprionibacterium acnes occurs in sufficient numbers, they could produce initiating antigenic molecules that promote the initiation of inflammation. Proprionibacterium acnes can produce proteinases, lipase, and hyaluronate lyase all of which may serve as the catalysts or initiators of the inflammatory infiltrate which has been shown to be composed of neutrophils and lymphocytes.
A number of treatments are presently known for treating acne, some more successful than others. Some modes of treatment have been mentioned above. There are two modes of treatment, topical and systemic.
Aside from treatments mentioned above, some additional systemic treatments for acne that are presently employed are: oral tetracycline; oral erythromycin; minocycline; doxycycline; oral trimethoprim-sulfamethoxazole and isotretinoin.
Those that have been suggested in the past and that are no longer generally employed include: antibacterial vaccines; estrogen therapy; dietary restrictions; and vitamin therapy (e.g. oral ingestion of vitamin A).
Some of the topical treatments that are presently employed are: topical erythromycin, clindamycin, benzoyl peroxide, 2% sulfur, 3% resorcinol, a tetracycline derivative (meclocycline sulfosalicylate 1%), 2% salicylic acid, and tretinoin.
Topical treatments that have been suggested in the past and that are no longer generally employed include: x-ray treatment; electric sparks; vitamin therapy; treatment with a plant extract as described in U.S. Pat. No. 4,803,069.
More specifically with respect to the topical use of certain specific antibiotics, a topical solution, ointment, and gel containing erythromycin is used. Also used is a topical solution, gel, and lotion containing clindamycin, and a cream containing meclocycline sulfosalicylate 1% (a tetracycline derivative).
Some of the undesirable side effects of orally administered antibiotics are abdominal cramps, black tongue, cough, diarrhea, fatigue, irritation of the mouth, loss of appetite, nausea, vomiting, fever, hearing loss, jaundice, rash, rectal and vaginal itching, and superinfection.
It is noted that erythromycin is produced by the bacterium Streptomyces erytheus and that erythromycin has a chemical structure that is substantially unique to erythromycin and its derivatives. The molecular weight of erythromycin A is 733.92. The empirical formula for erythromycin A is C.sub.37 H.sub.67 NO.sub.13 having a 60.55% carbon content, a 9.20% hydrogen content, a 1.91% nitrogen content, and a 28.34% oxygen content.
Clindamycin has a chemical structure indicated by its chemical name which is methyl 7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl]ami no]-1-thio-L-threo-alpha-D-galacto-octopyranoside. The molecular weight of clindamycin is 424.98. The empirical formula for clindamycin is C.sub.18 H.sub.337 ClN.sub.2 O.sub.5 S having a 50.87% carbon content, a 7.83% hydrogen content, a 8.34% chlorine content, a 6.59% nitrogen content, a 18.82% oxygen content, and a 7.54% sulfur content.
Other topical treatments for acne using antibiotics are described in the following Great Britain patents: neomycin, G. B. Pat. No. 1,054,124; erythromycin, G. B. Pat. No. 1,587,428; and erythromycin derivatives in conjunction with benzoyl peroxide, G. B. Pat. Nos. 2,088,717 and 2,090,135.
Still another topical treatment for acne, more specifically acne vulgaris, includes preparation of a hyaluronic acid derivative which is a bridged conjugate of hyaluronic acid (which is a linear polymer of N-acetyl glucosamine and glucuronic acid units) bonded to a bridging agent (which is cyanogen bromide) which, in turn, is bonded to the amino-nitrogen atom of the aminopenicillin, ampicillin. Thus, with this hyaluronic acid derivative, the amino-nitrogen of the aminopenicillin is no longer in the form of a primary amino group. This hyaluronic acid derivative is disclosed in Great Britain Published Application 2,207,142.
The formulation disclosed in Great Britain Published Application 2,207,142 may pose several significant problems. First, by reacting the bridging agent with the primary amino-nitrogen of the aminopenicillin, the effectiveness of the aminopenicillin may be severely reduced or even eliminated. More specifically, presently, all of the aminopenicillins that are approved for prescribing in the practice of medicine in the United States include an amino-nitrogen which is in the form of a primary amino group (the nitrogen atom of the primary amino group being bonded to two hydrogen atoms). Not one of these approved aminopenicillins has its characteristic primary amino group modified so that it is no longer a primary amino group.
Another significant potential problem posed by the hyaluronic acid derivative is disclosed in Great Britain Published Application 2,207,142 is the fact that a very toxic bridging agent, cyanogen bromide, is disclosed. Cyanogen bromide can cause toxic effects similar to those of hydrogen cyanide. Hydrogen cyanide may cause death from only a few minutes exposure to a concentration of approximately 300 ppm. (See Merck Index, Tenth Edition, 1983, pages 385 and 696) Lesser concentrations may cause headache, vertigo, nausea, and vomiting. With these potentially serious toxic side effects of cyanogen bromide, it may be undesirable if not risky to even employ the hyaluronic derivative disclosed in Great Britain Published Application 2,207,142. More specifically, on page 5, lines 3-5 of Great Britain Published Application 2,207,142, there is a teaching that a stringy precipitate (of a bridged hyaluronic acid/cyanogen bromide/ampicillin conjugate) is washed several times with absolute ethanol and dried in the air. Then, as disclosed on page 5, lines 16-26, the bridged hyaluronic acid/cyanogen bromide/ampicillin conjugate, having been incorporated in a conventional medium, is applied directly to the skin to treat acne vulgaris. What may be risky about using this bridged hyaluronic acid/cyanogen bromide/ampicillin conjugate is that a quantity of unreacted cyanogen bromide may remain as a residue in the precipitate after several rinses with absolute alcohol. Then, by applying some of this bridged hyaluronic acid/cyanogen bromide/ampicillin conjugate directly to the skin of patients, one may then be applying a residue of cyanogen bromide directly to the skin of patients.
For the reasons stated above with respect to the bridged hyaluronic acid/cyanogen bromide/ampicillin conjugate disclosed in Great Britain Published Application 2,207,142, it is desirable to avoid using an ampicillin in which the characteristic amino-nitrogen is not in the form of a primary amino group, and it is desirable to avoid using a material that may contain a toxic residue such as the bridging agent cyanogen bromide.
Still other topical treatments for acne using antibacterials are described in the following U. S. patents: an azole derivative in conjunction with benzoyl peroxide, U.S. Pat. No. 4,446,145, incorporated herein by reference; and metronidazole in a special gel as described in U.S. Pat. No. 4,837,378, incorporated herein by reference.